The importance of Clinical Trial Protocol in Drug Development and Approval

Clinical studies are a vital aspect of drug development and approval. In a clinical study, the protocol is critical as it is the single-most-important quality control tool for all aspects of a clinical trial. The protocol helps harmonize clinical studies conducted in a multi-center clinical trial where the collaboration of many investigators and their staff at multiple clinical study sites is involved. The protocol is a document that describes how a clinical trial will be conducted (the objective(s), design, methodology, statistical considerations and organization of a clinical trial). It ensures the trial subjects’ safety and the data’s integrity.

The significance of creating a harmonised Clinical Trial Protocol

Each organization has their protocol template/format. This difference in template/format or variability in core content among different sponsors contributes to inefficiencies and difficulties during regulatory submission, especially in searching, reviewing, and assessing clinical trial protocols. Thus, there is a need for a single harmonized protocol template which will help the sponsor or sponsor-investigator in the development of a complete protocol free from ambiguity, well-organized, and aligned with quality by design principles. By conveying information consistently and in the exact location across clinical trial protocols, a protocol template is intended to provide value to parties that include sponsors, investigators, clinical site personnel, trial participants, ethics committees, and regulators.

USFDA's M11 Guidance on Clinical Electronic Structured Harmonized Protocol (CESHARP) and Protocol Template Release.

On 22nd December 2022, USFDA released M11- technical specification- clinical electronic structured harmonized protocol (CESHARP). This guidance aims to create an international standard for the content and exchange of clinical trial protocol information, facilitating review and assessment by regulators, sponsors, ethical oversight bodies, investigators, and other stakeholders. In addition, the protocol template was released for comments from various stakeholders.

CESHARP received feedback from the industry

As of February 2023, the document received 23 documents with comments from various pharmaceutical industry groups as well as universities such as Biotechnology Innovation Organization (BIO), LFB Biotechnology, CRISPR Therapeutics, Certara, Coalition for Epidemic Preparedness Innovations (CEPI), Pharmaceutical Research and Manufacturers of America (PhRMA), University of Pennsylvania, etc.

Some of the Critical Findings Expressed by the Community included:

  1. Data sharing- The section on Data Protection is covered in the protocol template. In many cases, participants are open to making their data available beyond the scope of the original study and hence need to include a data-sharing section in the protocol template.
  2. The need for “Diversity Plans to Improve Enrolment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” to be implemented in the protocol.
  3. There is a need to include details for procedures for reporting urgent safety measures, grave breaches, and changing risk-benefit assessments due to unexpected events as per EU Clinical Trials Regulation 536/2014.
  4. There is a need to include Protocol Title and Health Authority Identifier as these details are required in the synopsis per EU CTR and are included in the Common protocol template
  5. Template to harmonize to include phase 1 trials as a template primarily focuses on confirmatory trials, including estimations.
  6. Definition of the protocol is to be broadened to cover the purpose of the trial and its design.
  7. For alignment with ICH E8(R1, the term ‘trial’ is to be replaced by “Study” as it is a broader term and should be used to reflect the diverse types of studies that are in scope for the protocol template
  8. Use of more clear terminology such as “masking” instead of “blinding”, “healthy participants” rather than “healthy volunteers, etc.
  9. Recommendation of rearranging the title page to include the Short Protocol Title and Acronym following the Full Protocol Title.

Clinical Electronic Structured Harmonized Protocol (CESHARP): a rocky start with a promising future

The typical comment from various stakeholders was to use explicit/consistent terminologies and uniform abbreviations. Additionally, comments regarding inputs from other international guidelines were suggested to be considered. Thus, it would be prudent to see the changes in the protocol template after incorporating the comments received from various stakeholders. Industry bodies and universities expect a more robust protocol template harmonising different clinical study phases and various regulatory agencies from the released M11- technical specification: clinical electronic structured harmonized protocol (CESHARP).

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Industry bodies commented on USFDA released M11: technical specification – clinical electronic structured harmonized protocol (CESHARP)